The gut microbiota and coronary artery calcification in Japanese men.

BACKGROUND: The gut microbiota differs between patients with coronary artery disease (CAD) and healthy controls; however, it currently remains unclear whether these differences exist prior to the onset of CAD. We herein investigated the gut microbiota associated with subclinical coronary artery calcification (CAC) in a Japanese population. METHODS: A total of 663 Japanese men were enrolled in this cross-sectional study. Computed tomography and gut microbiology tests were performed, and CAC scores were calculated using the Agatston method. Participants were categorized into 4 groups based on their CAC scores: CAC = 0, 0

Differential Prognostic Impact of Clinical Congestion between Preserved versus Reduced Ejection Fraction in Patients Hospitalized for Acute Decompensated Heart Failure: Findings from the Japanese KCHF registry.

BACKGROUNDS: Most patients hospitalized for heart failure (HF) present with signs of congestion. Prognostic significance of clinical congestion may vary depending on left ventricular ejection fraction (LVEF). This study aims to investigate the prognostic impact of congestion across different LVEF categories. METHODS AND RESULTS: Composite congestion scores (CCS) (0-9) derived from the severity of edema, jugular venous pressure, and orthopnea, were analyzed on admission and at discharge in 3787 patients hospitalized for HF (LVEF≥40%: n=2347, LVEF<40%: n=1440). The median admission CCS was 4 in both LVEF strata (P=0.64). Adjusted HRs (95%CI) of the moderate [CCS 4-6] and severe congestion [7-9] groups relative to the mild congestion [0-3] group on admission for a composite of all-cause death or HF re-hospitalization were 1.20 (1.04-1.39, P=0.01) and 1.54 (1.27-1.86, P<0.001) in the LVEF≥40% stratum, and 1.20 (1.01-1.44, P=0.04) and 0.82 (0.61-1.07, P=0.14) in the LVEF<40% stratum, respectively (Pinteraction<0.001). 16% of the patients with LVEF ≥40% and 14% with LVEF <40% had residual congestion (CCS ≥1) at discharge, which was associated with respective adjusted HR of 1.40 (1.18-1.65, P <0.001) and 1.25 (0.98-1.58, P=0.07) for post-discharge death or HF re-hospitalization (Pinteraction=0.63). CONCLUSION: The severity of clinical congestion on admission was associated with adverse clinical outcomes in patients with LVEF ≥40%, but no in those with LVEF <40%. These findings warrant further studies to better understand the detailed profile of congestion across the LVEF spectrum.

Effect of empagliflozin on ventricular arrhythmias in patients with type 2 diabetes treated with an implantable cardioverter-defibrillator: the EMPA-ICD trial.

BACKGROUND: Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of hospitalization for heart failure and cardiovascular death with type 2 diabetes; however, their effect on arrhythmias is unclear. The purpose of this study was to investigate the effects of empagliflozin on ventricular arrhythmias in patients with type 2 diabetes. METHODS: A total of 150 patients with type 2 diabetes who were treated with an implantable cardioverter-defibrillator or cardiac resynchronization therapy defibrillator (ICD/CRT-D) were randomized to once-daily empagliflozin or placebo for 24 weeks. The primary endpoint was the change in the number of ventricular arrhythmias from the 24 weeks before to the 24 weeks during treatment. Secondary endpoints included the change in the number of appropriate device discharges and other values. RESULTS: In the empagliflozin group, the number of ventricular arrhythmias recorded by ICD/CRT-D decreased by 1.69 during treatment compared to before treatment, while in the placebo group, the number increased by 1.79. The coefficient for the between-group difference was - 1.07 (95% confidence interval [CI] - 1.29 to - 0.86; P < 0.001). The change in the number of appropriate device discharges during and before treatment was 0.06 in the empagliflozin group and 0.27 in the placebo group, with no significant difference between the groups (P = 0.204). Empagliflozin was associated with an increase in blood ketones and hematocrit and a decrease in blood brain natriuretic peptide and body weight. CONCLUSIONS: In patients with type 2 diabetes treated with ICD/CRT-D, empagliflozin reduces the number of ventricular arrhythmias compared with placebo. Trial registration jRCTs031180120.

Plasma ANGPTL8 Levels and Risk for Secondary Cardiovascular Events in Japanese Patients With Stable Coronary Artery Disease Receiving Statin Therapy.

BACKGROUND: The ability to predict secondary cardiovascular events could improve health of patients undergoing statin treatment. Circulating ANGPTL8 (angiopoietin-like protein 8) levels, which positively correlate with proatherosclerotic lipid profiles, activate the pivotal proatherosclerotic factor ANGPTL3. Here, we assessed potential association between circulating ANGPTL8 levels and risk of secondary cardiovascular events in statin-treated patients. METHODS: We conducted a biomarker study with a case-cohort design, using samples from a 2018 randomized control trial known as randomized evaluation of high-dose (4 mg/day) or low-dose (1 mg/day) lipid-lowering therapy with pitavastatin in coronary artery disease (REAL-CAD [Randomized Evaluation of Aggressive or Moderate Lipid-Lowering Therapy With Pitavastatin in Coronary Artery Disease])." From that study's full analysis set (n=12 413), we selected 2250 patients with stable coronary artery disease (582 with the primary outcome, 1745 randomly chosen, and 77 overlapping subjects). A composite end point including cardiovascular-related death, nonfatal myocardial infarction, nonfatal ischemic stroke, or unstable angina requiring emergent admission was set as a primary end point. Circulating ANGPTL8 levels were measured at baseline and 6 months after randomization. RESULTS: Over a 6-month period, ANGPTL8 level changes significantly decreased in the high-dose pitavastatin group, which showed 19% risk reduction of secondary cardiovascular events compared with the low-dose group in the REAL-CAD [Randomized Evaluation of Aggressive or Moderate Lipid-Lowering Therapy With Pitavastatin in Coronary Artery Disease] study. In the highest quartiles, relative increases in ANGPTL8 levels were significantly associated with increased risk for secondary cardiovascular events, after adjustment for several cardiovascular disease risk factors and pitavastatin treatment (hazard ratio in Q4, 1.67 [95% CI, 1.17-2.39). Subgroup analyses showed relatively strong relationships between relative ANGPTL8 increases and secondary cardiovascular events in the high-dose pitavastatin group (hazard ratio in Q4, 2.07 [95% CI, 1.21-3.55]) and in the low ANGPTL8 group at baseline (166

Radiofrequency Catheter Ablation for Atrial Fibrillation Patients on Hemodialysis (From the Kansai Plus Atrial Fibrillation Registry)　- Clinical Impact of Early Recurrence.

BACKGROUND: Catheter ablation (CA) for atrial fibrillation (AF) in patients on hemodialysis (HD) is reported to have a high risk of late recurrence (LR). However, the relationship between early recurrence (ER) within a 90-day blanking period after CA in AF patients and LR in HD patients remains unclear. METHODS AND RESULTS: Of the 5,010 patients in the Kansai Plus Atrial Fibrillation Registry, 5,009 were included in the present study. Of these patients, 4,942 were not on HD (non-HD group) and 67 were on HD (HD group). HD was an independent risk factor for LR after the initial CA (adjusted hazard ratio 1.6; 95% confidence interval 1.1-2.2; P=0.01). In patients with ER, the rate of sinus rhythm maintenance at 3 years after the initial CA was significantly lower in the HD than non-HD group (11.4% vs. 35.4%, respectively; log-rank P=0.004). However, in patients without ER, there was no significant difference in the rate of sinus rhythm maintenance at 3 years between the HD and non-HD groups (67.7% vs. 74.5%, respectively; log-rank P=0.62). CONCLUSIONS: ER in HD patients was a strong risk factor for LR. However, even HD patients could expect a good outcome without ER after the initial CA.

The two therapeutic strategies of surgical intervention and medical management in a patient with enhanced-fibrinolytic type of disseminated intravascular coagulation after aortic replacement for Stanford type A aortic dissection with chronic heart and renal failure.

BACKGROUND: Management of the enhanced-fibrinolytic type of disseminated intravascular coagulation (DIC) caused by aortic disorders is the two strategies of surgical intervention and medical treatment based on the patient's age and comorbidities. CASE PRESENTATION: An 81-year-old woman with a history of two previous aortic surgeries and chronic heart and renal failure was admitted for uncontrollable subcutaneous hemorrhage. The hemorrhage was caused by the enhanced-fibrinolytic type of disseminated intravascular coagulation (DIC) caused by periprosthetic graft hematoma after aortic replacement for Stanford type A aortic dissection. Open thoracic hemostasis temporarily controlled the subcutaneous hemorrhage, but she was readmitted for the recurrence seven months after discharge. On the second admission, the combination of anticoagulant and antifibrinolytic agents was successful. CONCLUSION: Management of the enhanced-fibrinolytic type of DIC caused by aortic disorders is important of a successful combination of surgical and medical therapy tailored the patient's condition.

Statins use and recurrent venous thromboembolism in the direct oral anticoagulant era: insight from the COMMAND VTE Registry-2.

Statins were reported to have a potential effect of primary prevention of venous thromboembolism (VTE), although that of secondary prevention remains uncertain. To investigate the association between statins use and recurrent VTE in the current era. The COMMAND VTE Registry-2 is a multicenter registry enrolling 5,197 consecutive VTE patients among 31 centers in Japan between January 2015 and August 2020. We divided the entire cohort into 2 groups according to statins use at the time of discharge; the statins (N = 865) and no statins groups (N = 4332). The statins group was older (72.9 vs. 66.7 years, P < 0.001), and less often had active cancer (22.0% vs. 30.4%, P < 0.001). The cumulative incidence of discontinuation of anticoagulation was significantly lower in the statins group (60.3% vs. 52.6%, Log-rank P < 0.001). The cumulative 5-year incidence of recurrent VTE was significantly lower in the statins group (6.8% vs. 10.1%, Log-rank P = 0.01). Even after adjusting for the confounders, the lower risk of the statins group relative to the no statins group remained significant for recurrent VTE (HR 0.65, 95% CI 0.45-0.91, P = 0.01). The cumulative 5-year incidence of major bleeding was significantly lower in the statins group (12.2% vs. 14.1%, Log-rank P = 0.04), although, after adjusting for the confounders, the risk of the statins group relative to the no statins group turned to be insignificant (HR 0.77, 95% CI 0.59-1.00, P = 0.054). In this large real-world VTE registry, statins use was significantly associated with a lower risk for the recurrent VTE in the current era.

Difference in one-year late lumen loss between high- and low-dose paclitaxel-coated balloons for femoropopliteal disease.

The objective of the study is to investigate the difference in 1-year late lumen loss (LLL) between the high- (IN.PACT Admiral) and low-dose (Lutonix) paclitaxel-coated balloon (PCB). Although a recent randomized clinical trial demonstrated no difference in efficacy endpoint between high- and low-dose PCB, it remains unclear whether high-dose PCB was superior to low-dose PCB in actual clinical practice. We enrolled 64 patients with 67 de novo femoropopliteal lesions who underwent PCB angioplasty at Kokura Memorial Hospital from May 2014 to March 2020 and subsequent follow-up angiography after 1 year. The primary endpoint was 1-year LLL, whereas the secondary endpoints were binary restenosis and clinically driven target lesion revascularization (CD-TLR) after 1 year. The high- and low-dose PCB groups had 45 and 22 lesions, respectively. Although the low-dose PCB group had higher rates of coronary artery disease, hemodialysis, and chronic limb-threatening ischemia than the high-dose PCB group, the latter had a longer lesion length and more lesions with a TASC classification C or D than the former. The high-dose PCB group had a significantly lower LLL than the low-dose PCB group (0.40 ± 1.05 vs. 1.19 ± 1.03 mm; P = 0.003, respectively). Moreover, the high-dose PCB group had significantly lower rates of binary restenosis at 1 year than the low-dose PCB group (22.2% vs. 50.0%; P = 0.02, respectively). Moreover, negative LLL was only observed in the high-dose PCB group (33.3% vs. 0%, P = 0.005). The high-dose PCB group had a significantly lower LLL than the low-dose PCB group.

Rationale and study design of the GOREISAN for heart failure (GOREISAN-HF) trial: A randomized clinical trial.

BACKGROUND: The decongestion strategy using loop diuretics is essential for improving signs and symptoms of heart failure (HF). However, chronic use of loop diuretics in HF has been linked to worsening renal function and adverse clinical outcomes in a dose-dependent manner. Goreisan, a traditional Japanese herbal medicine, has a long history of use in Japan for regulating body fluid homeostasis and has been recognized as causing less adverse outcomes such as dehydration in contrast to loop diuretics in clinical practice. Therefore, we designed the GOREISAN-HF trial to evaluate the long-term effects of a new decongestion strategy adding Goreisan to usual care in patients with HF and volume overload. METHODS: The GOREISAN-HF trial is an investigator-initiated, multicenter, pragmatic, randomized, comparative effectiveness trial in which we will enroll 2,192 patients hospitalized for HF at 68 hospitals in Japan. All study participants will be randomly assigned to either a decongestion strategy that adds Goreisan at a dose of 7.5 g daily on top of usual care or usual care alone. Investigators have the flexibility to change the existing diuretic regimen in both groups. The primary end point is the improvement rate of cardiac edema at 12-month follow-up, and the co-primary end point is a composite of all-cause death or hospitalization up to the end of the planned follow-up period. Secondary end points include longitudinal changes in patient-reported outcomes, loop diuretics dose, and renal function. CONCLUSIONS: The GOREISAN-HF is the first large-scale randomized pragmatic trial to assess the efficacy and safety of a new congestion control strategy adding Goreisan to usual care in patients with HF and volume overload. REGISTRATION NUMBER: NCT04691700.

Prognostic Value of the Severity of Clinical Congestion in Patients Hospitalized for Decompensated Heart Failure: Findings From the Japanese KCHF Registry.

BACKGROUND: Congestion is a leading cause of hospitalization and a major therapeutic target in patients with heart failure (HF). Clinical practice in Japan is characterized by a long hospital stay, which facilitates more extensive decongestion during hospitalization. We herein examined the time course and prognostic impact of clinical congestion in a large contemporary Japanese cohort of HF. METHODS AND RESULTS: Peripheral edema, jugular venous pressure, and orthopnea were graded on a standardized 4-point scale (0-3) in 3787 hospitalized patients in a Japanese cohort of HF. Composite Congestion Scores (CCS) on admission and at discharge were calculated by summing individual scores. The primary outcome was a composite of all-cause death or HF hospitalization. The median admission CCS was 4 (interquartile range, 3-6). Overall, 255 patients died during the median hospitalization length of 16 days, and 1395 died or were hospitalized for HF over a median postdischarge follow-up of 396 days. The cumulative 1-year incidence of the primary outcome increased at higher tertiles of congestion on admission (32.5%, 39.3%, and 41.0% in the mild [CCS ≤3], moderate [CCS = 4 or 5], and severe [CCS ≥6] congestion groups, respectively, log-rank P < .001). The adjusted hazard ratios of moderate and severe congestion relative to mild congestion were 1.205 (95% confidence interval [CI], 1.065-1.365; P = .003) and 1.247 (95% CI, 1.103-1.410; P < .001), respectively. Among 3445 patients discharged alive, 85% had CCS of 0 (complete decongestion) and 15% had a CCS of 1 or more (residual congestion) at discharge. Although residual congestion predicted a risk of postdischarge death or HF hospitalization (adjusted hazard ratio, 1.314 [1.145-1.509]; P < .001), the admission CCS correlated with the risk of postdischarge death or HF hospitalization, even in the complete decongestion group. No correlation was observed for postdischarge death or HF hospitalization between residual congestion at discharge and admission CCS (P for the interaction = .316). CONCLUSIONS: In total, 85% of patients were discharged with complete decongestion in Japanese clinical practice. Clinical congestion, on admission and at discharge, was of prognostic value. The severity of congestion on admission was predictive of adverse outcomes, even in the absence of residual congestion. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT02334891 (NCT02334891) https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000017241 (UMIN000015238).

Ten-year clinical outcomes from a randomized trial comparing new-generation everolimus-eluting stent versus first-generation Sirolimus-eluting stent: Results from the RESET extended study.

BACKGROUND: New-generation drug-eluting stents (DES) achieved technological innovations and reported clinical advantages as compared with first-generation DES in clinical trials with 3-5 years follow-up. However, detailed clinical outcome data in very long-term follow-up is still scarce. OBJECTIVES: To evaluate 10-year clinical outcomes after first- and new-generation DES implantation. METHODS: In this extende follow-up study of the RESET, which is a largest randomized trial comparing everolimus-eluting stent (EES) with Sirolimus-eluting stent (SES), the study population consisted of 2892 patients from 84 centers. The primary efficacy and safety endpoints were target lesion revascularization (TLR) and a composite of death or myocardial infarction (MI), respectively. Complete 10-year follow-up was achieved in 87.9% of patients. RESULTS: Cumulative 10-year incidences of TLR and non-TLR were not significantly different between EES and SES (13.9% vs. 15.7%, Log-rank p = 0.20, and 33.4% vs. 31.3%, Log-rank p = 0.30). The cumulative 10-year incidence of death/MI was also not significantly different between the groups (32.5% vs. 34.4%, Log-rank p = 0.18). Cumulative 10-year incidence of definite stent thrombosis was numerically lower in EES than in SES (1.0% vs. 1.7%, Log-rank p = 0.16). The lower risk of EES relative to SES was significant for a composite endpoint of target lesion failure (TLF: 19.6% vs. 24.9%, Log-rank p = 0.001) and target vessel failure (TVF: 26.7% vs. 31.4%, Log-rank p = 0.006). CONCLUSION: During 10-year of follow-up, the risks for primary efficacy and safety endpoints were not significantly different between new-generation EES and first-generation SES, although EES compared with SES was associated with a lower risk for composite endpoints such as TLF and TVF.

Control of Diabetes Mellitus and Long-Term Prognosis in Stroke Patients: The Shiga Stroke and Heart Attack Registry.

BACKGROUND: The relationship between diabetes control status and long-term prognosis after stroke incidence remains unclear. This study aimed to investigate the effect of diabetes status at admission on long-term survival in patients with first-ever stroke. METHODS: A retrospective cohort study was conducted based on the Shiga Stroke and Heart Attack Registry in Japan. Patients were classified according to their diabetes status and glycated hemoglobin (HbA1c) value at hospital admission into the following: (1) free of diabetes (no history of diabetes and HbA1c <6.5%); (2) good control (history of diabetes and HbA1c <7%; free of history and 6.5% ≤HbA1c <7%); and (3) poor control (with or without a history of diabetes and HbA1c ≥7%). Multivariable Cox regression models were used to evaluate the association between diabetes status and long-term survival from stroke onset. Additionally, we also evaluated the association between diabetes status and conditional survival, beginning 29 days after stroke onset. RESULTS: A total of 6,331 first-ever stroke patients were eligible for this study. Among study patients, the mean (±SD) age was 72.85 ± 13.19 years, and the mean (±SD) follow-up year was 2.76 ± 1.66 years; additionally, 42.09% of patients were women. Among patients with all strokes, considering the free-of-diabetes group as the reference group, the adjusted hazard ratio (95% confidence interval) for mortality was 1.26 (1.10, 1.44) in the good control group and 1.22 (1.05, 1.41) in the poor control group. Among patients with ischemic stroke, the adjusted hazard ratio was 1.24 (1.06, 1.46) in good control group and 1.27 (1.08, 1.50) in poor control group. After excluding patients who died within 28 days, the adjusted hazard ratio for conditional mortality in the poor control group was 1.31 (1.12, 1.54) among all stroke patients and 1.29 (1.08, 1.54) among ischemic stroke patients. No significant associations were observed between diabetic status and long-term mortality in intracerebral hemorrhage patients. CONCLUSIONS: The findings suggest that first-ever stroke patients with diabetes exhibited a higher risk of all-cause mortality than those without diabetes, particularly in the overall stroke and ischemic stroke populations. Additionally, in stroke populations after 28 days of onset, high risk of long-term mortality was stated in stroke patients with poor HbA1c control.

Long-Term Clinical Outcome After Alcohol Septal Ablation and Its Periprocedural Predictive Factors in Japan　- A Retrospective Observational Study.

BACKGROUND: Evidence is limited regarding long-term clinical outcomes after alcohol septal ablation (ASA) for patients with hypertrophic obstructive cardiomyopathy and its periprocedural predictive factors in Japan.Methods and Results: This retrospective observational study included 44 patients who underwent ASA between 1998 and 2022 in a single center. We evaluated the periprocedural change in variables and long-term clinical outcomes after the procedure. The primary outcome was a composite of cardiovascular death or hospitalization for heart failure. The secondary outcome was all-cause death. Using multivariable Poisson regression with robust error variance, we predicted underlying periprocedural factors related to primary outcome development. ASA decreased the median pressure gradient at the left ventricular outflow tract from 88 to 33 mmHg and reduced moderate or severe mitral regurgitation (MR), present in 53% of patients before ASA, to 16%. Over a median 6-year follow-up, the cumulative incidence of the primary outcome at 5 and 10 years was 16.5% and 25.6%, respectively. After multivariable analysis, moderate or severe MR after ASA was significantly associated with the primary outcome (relative risk 8.78; 95% confidence interval 1.34-57.3; P=0.024). All-cause mortality after ASA was 15.1% and 28.9% at 5 and 10 years, respectively. CONCLUSIONS: This study presents long-term clinical outcomes after ASA in Japan. Moderate or severe MR after ASA was significantly associated with the composite of cardiovascular death or hospitalization for heart failure.

Discriminative Ability of Dynamic Chest Radiography to Identify Left Ventricular Dysfunction.

BACKGROUND: Dynamic chest radiography (DCR) produces sequential radiographs within a short examination time. It is also inexpensive and only uses a low dose of radiation. Because of the lack of reports of evaluating cardiac function using DCR in humans, we investigated its discriminative ability for left ventricular (LV) dysfunction in a study cohort.Methods and Results: We analyzed the DCR pixel values of 4 circular regions of interest (ROIs) in the hearts of 61 patients with cardiovascular disease and 10 healthy volunteers. We evaluated the relationship between changes in pixel value in the heart and the LV ejection fraction (LVEF) by echocardiography. We constructed receiver operating characteristic (ROC) curves to evaluate whether the percent change in pixel value (%∆pixel value) could be used to identify patients with reduced LVEF. A total of 21 patients had reduced LVEF (LVEF <50%), and 40 had preserved LVEF (LVEF ≥50%). The correlation between LVEF and %∆pixel value in each ROI was significant, and the area under the ROC curve of the %∆pixel values for identifying patients with reduced LVEF was satisfactory (0.808-0.827) in 3 ROIs where the entire circular area was within the cardiac shadow. CONCLUSIONS: LV dysfunction can be detected by changes in the pixel value on DCR.

Clopidogrel Use in CYP2C19 Loss-of-Function Carriers With High Bleeding Risk After Percutaneous Coronary Intervention.

BACKGROUND: It is not known whether clopidogrel use in cytochrome P450 (CYP) 2C19 loss-of-function (LOF) carriers with high bleeding risk (HBR) contributes to adverse outcomes after percutaneous coronary intervention (PCI).Methods and Results: This retrospective observational study included 618 consecutive patients with available CYP2C19 polymorphism information who underwent PCI between September 2014 and August 2021. Patients with HBR (319 [52%] met the Academic Research Consortium definition) were divided into 2 groups according to P2Y12inhibitor action, namely decreased (i.e., clopidogrel in CYP2C19 LOF carriers) and retained (i.e., clopidogrel in CYP2C19 LOF non-carriers or prasugrel regardless of CYP2C19 polymorphisms), and clinical outcomes at 1 year were compared using inverse probability-weighted Cox proportional hazard regression. The primary ischemic outcome (a composite of cardiovascular death, myocardial infarction, or ischemic stroke) was significantly higher in the decreased than retained group (10.2% vs. 3.0%; adjusted hazard ratio [aHR] 2.78; 95% confidence interval [CI] 1.40-5.52; P=0.004). The primary bleeding outcome (Bleeding Academic Research Consortium 3 or 5) did not differ significantly between the decreased and retained groups (3.4% vs. 6.9%, respectively; aHR 0.48; 95% CI 0.22-1.01; P=0.054). There were no interactions between the treatment groups and HBR status in primary ischemic and bleeding outcomes. CONCLUSIONS: Among patients with HBR, clopidogrel use in CYP2C19 LOF carriers was significantly associated with increased ischemic events after PCI.

Epidemiology of Acute Aortic Dissection in a General Population of 1.4 Million People in Japan　- Shiga Stroke and Heart Attack Registry.

BACKGROUND: Acute aortic dissection (AAD) is a life-threatening cardiovascular disease, with a reported incidence rate ranging from 2.5 to 7.2 per 100,000 person-years in several population-based registries in Western countries, but epidemiological data are lacking in Japan.Methods and Results: The Shiga Stroke and Heart Attack Registry is an ongoing multicenter population-based registry of cerebro-cardiovascular diseases. We enrolled patients who developed AAD, defined by any imaging examination method from 2014 to 2015 in Shiga Prefecture. Death certificates were used to identify cases that were not registered at acute care hospitals. The incidence rates of AAD were calculated by age categories and adjusted using standard populations for comparison. We evaluated differences in patient characteristics between Stanford type A-AAD and type B-AAD subtypes. A total of 402 incident cases with AAD were analyzed. The age-adjusted incidence rates using the 2015 Japanese population and the 2013 European Standard Population were 15.8 and 12.2 per 100,000 person-years, respectively. Compared with cases of type B-AAD, those with type A-AAD were older (75.0 vs. 69.9 years, P=0.001) and more likely to be women (62.3% vs. 28.6%, P<0.001). CONCLUSIONS: Population-based incidence rates of AAD in Japan appear to be higher than in previous reports from Western countries. Incident cases with type A-AAD were older and female predominance.

Calmodulinopathy in Japanese Children　- Their Cardiac Phenotypes Are Severe and Show Early Onset in Fetal Life and Infancy.

BACKGROUND: Cardiac calmodulinopathy, characterized by a life-threatening arrhythmia and sudden death in the young, is extremely rare and caused by genes encoding calmodulin, namely calmodulin 1 (CALM1), CALM2, and CALM3.Methods and Results: We screened 195 symptomatic children (age 0-12 years) who were suspected of inherited arrhythmias for 48 candidate genes, using a next-generation sequencer. Ten probands were identified as carrying variants in any of CALM1-3 (5%; median age 5 years), who were initially diagnosed with long QT syndrome (LQTS; n=5), catecholaminergic polymorphic ventricular tachycardia (CPVT; n=3), and overlap syndrome (n=2). Two probands harbored a CALM1 variant and 8 probands harbored 6 CALM2 variants. There were 4 clinical phenotypes: (1) documented lethal arrhythmic events (LAEs): 4 carriers of N98S in CALM1 or CALM2; (2) suspected LAEs: CALM2 p.D96G and D132G carriers experienced syncope and transient cardiopulmonary arrest under emotional stimulation; (3) critical cardiac complication: CALM2 p.D96V and p.E141K carriers showed severe cardiac dysfunction with QTc prolongation; and (4) neurological and developmental disorders: 2 carriers of CALM2 p.E46K showed cardiac phenotypes of CPVT. Beta-blocker therapy was effective in all cases except cardiac dysfunction, especially in combination with flecainide (CPVT-like phenotype) and mexiletine (LQTS-like). CONCLUSIONS: Calmodulinopathy patients presented severe cardiac features, and their onset of LAEs was earlier in life, requiring diagnosis and treatment at the earliest age possible.

Low-Density Lipoprotein Cholesterol Levels on Statins and Cardiovascular Event Risk in Stable Coronary Artery Disease　- An Observation From the REAL-CAD Study.

BACKGROUND: The relationship between very low on-treatment low-density lipoprotein cholesterol (LDL-C) level and cardiovascular event risk is still unclear in patients receiving the same doses of statins.Methods and Results: From the REAL-CAD study comparing high-dose (4 mg/day) with low-dose (1 mg/day) pitavastatin therapy in patients with stable coronary artery disease, 11,105 patients with acceptable statin adherence were divided into 3 groups according to the on-treatment LDL-C level at 6 months (<70 mg/dL, 70-100 mg/dL, and ≥100 mg/dL). The primary outcome measure was a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal ischemic stroke, or unstable angina requiring emergent admission. The adjusted risks of the LDL-C <70 mg/dL group relative to the LDL-C 70-100 mg/dL group (reference) was not significantly different for the primary outcome measure in both 1 mg/day and 4 mg/day strata (HR 0.84, 95% CI 0.58-1.18, P=0.32, and HR 1.25, 95% CI 0.88-1.79, P=0.22). The adjusted risk of the LDL-C ≥100 mg/dL group relative to the reference group was not significant for the primary outcome measure in the 1 mg/day stratum (HR 0.82, 95% CI 0.60-1.11, P=0.21), whereas it was highly significant in the 4 mg/day stratum (HR 3.32, 95% CI 2.08-5.17, P<0.001). CONCLUSIONS: A very low on-treatment LDL-C level (<70 mg/dL) was not associated with lower cardiovascular event risk compared with moderately low on-treatment LDL-C level (70-100 mg/dL) in patients receiving the same doses of statins.

Polypharmacy and Bleeding Outcomes After Percutaneous Coronary Intervention.

BACKGROUND: Polypharmacy was reported to be associated with major bleeding in various populations. However, there are no data on polypharmacy and its association with bleeding in patients undergoing percutaneous coronary intervention (PCI).Methods and Results: Among 12,291 patients in the CREDO-Kyoto PCI Registry Cohort-3, we evaluated the number of medications at discharge and compared major bleeding, defined as Bleeding Academic Research Consortium Type 3 or 5 bleeding, across tertiles (T1-3) of the number of medications. The median number of medications was 6, and 88.0% of patients were on ≥5 medications. The cumulative 5-year incidence of major bleeding increased incrementally with increasing number of medications (T1 [≤5 medications] 12.5%, T2 [6-7] 16.5%, and T3 [≥8] 20.4%; log-rank P<0.001). After adjusting for confounders, the risks for major bleeding of T2 (hazard ratio [HR] 1.21; 95% confidence interval [CI] 1.08-1.36; P=0.001) and T3 (HR 1.27; 95% CI 1.12-1.45; P<0.001) relative to T1 remained significant. The adjusted risks of T2 and T3 relative to T1 were not significant for a composite of myocardial infarction or ischemic stroke (HR 0.95 [95% CI 0.83-1.09; P=0.47] and HR 1.06 [95% CI 0.91-1.23; P=0.48], respectively). CONCLUSIONS: In a real-world population of patients undergoing PCI, approximately 90% were on ≥5 medications. Increasing number of medications was associated with a higher adjusted risk for major bleeding, but not ischemic events.

Sex Differences in Clinical Outcomes After Percutaneous Coronary Intervention.

BACKGROUND: There is a scarcity of studies comparing the clinical outcomes after percutaneous coronary intervention (PCI) for women and men stratified by the presentation of acute coronary syndromes (ACS) or stable coronary artery disease (CAD).Methods and Results: The study population included 26,316 patients who underwent PCI (ACS: n=11,119, stable CAD: n=15,197) from the CREDO-Kyoto PCI/CABG registry Cohort-2 and Cohort-3. The primary outcome was all-cause death. Among patients with ACS, women as compared with men were much older. Among patients with stable CAD, women were also older than men, but with smaller difference. The cumulative 5-year incidence of all-cause death was significantly higher in women than in men in the ACS group (26.2% and 17.9%, log rank P<0.001). In contrast, it was significantly lower in women than in men in the stable CAD group (14.2% and 15.8%, log rank P=0.005). After adjusting confounders, women as compared with men were associated with significantly lower long-term mortality risk with stable CAD but not with ACS (hazard ratio [HR]: 0.75, 95% confidence interval [CI]: 0.69-0.82, P<0.001, and HR: 0.92, 95% CI: 0.84-1.01, P=0.07, respectively). There was a significant interaction between the clinical presentation and the mortality risk of women relative to men (interaction P=0.002). CONCLUSIONS: Compared with men, women had significantly lower adjusted mortality risk after PCI among patients with stable CAD, but not among those with ACS.